Enhancing selectivity of minimally invasive peripheral nerve interfaces using combined stimulation and high frequency block: from design to application

The discovery of the excitable property of nerves was a fundamental step forward in our knowledge of the nervous system and our ability to interact with it. As the injection of charge into tissue can drive its artificial activation, devices have been conceived that can serve healthcare by substituting the input or output of the peripheral nervous system when damage or disease has rendered it inaccessible or its action pathological. Applications are far-ranging and transformational as can be attested by the success of neuroprosthetics such as the cochlear implant. However, the body’s immune response to invasive implants have prevented the use of more selective interfaces, leading to therapy side-effects and off-target activation. The inherent tradeoff between the selectivity and invasiveness of neural interfaces, and the consequences thereof, is still a defining problem for the field. More recently, continued research into how nervous tissue responds to stimulation has led to the discovery of High Frequency Alternating Current (HFAC) block as a stimulation method with inhibitory effects for nerve conduction. While leveraging the structure of the peripheral nervous system, this neuromodulation technique could be a key component in efforts to improve the selectivity-invasiveness tradeoff and provide more effective neuroprosthetic therapy while retaining the safety and reliability of minimally invasive neural interfaces. This thesis describes work investigating the use of HFAC block to improve the selectivity of peripheral nerve interfaces, towards applications such as bladder control or vagus nerve stimulation where selective peripheral nerve interfaces cannot be used, and yet there is an unmet need for more selectivity from stimulation-based therapy. An overview of the underlying neuroanatomy and electrophysiology of the peripheral nervous system combined with a review of existing electrode interfaces and electrochemistry will serve to inform the problem space. Original contributions are the design of a custom multi-channel stimulator able to combine conventional and high frequency stimulation, establishing a suitable experimental platform for ex-vivo electrophysiology of the rat sciatic nerve model for HFAC block, and exploratory experiments to determine the feasibility of using HFAC block in combination with conventional stimulation to enhance the selectivity of minimally-invasive peripheral nerve interfaces.Open Acces

VLSI Circuits for Bidirectional Neural Interfaces

Medical devices that deliver electrical stimulation to neural tissue are important clinical tools that can augment or replace pharmacological therapies. The success of such devices has led to an explosion of interest in the field, termed neuromodulation, with a diverse set of disorders being targeted for device-based treatment. Nevertheless, a large degree of uncertainty surrounds how and why these devices are effective. This uncertainty limits the ability to optimize therapy and gives rise to deleterious side effects. An emerging approach to improve neuromodulation efficacy and to better understand its mechanisms is to record bioelectric activity during stimulation. Understanding how stimulation affects electrophysiology can provide insights into disease, and also provides a feedback signal to autonomously tune stimulation parameters to improve efficacy or decrease side-effects. The aims of this work were taken up to advance the state-of-the-art in neuro-interface technology to enable closed-loop neuromodulation therapies. Long term monitoring of neuronal activity in awake and behaving subjects can provide critical insights into brain dynamics that can inform system-level design of closed-loop neuromodulation systems. Thus, first we designed a system that wirelessly telemetered electrocorticography signals from awake-behaving rats. We hypothesized that such a system could be useful for detecting sporadic but clinically relevant electrophysiological events. In an 18-hour, overnight recording, seizure activity was detected in a pre-clinical rodent model of global ischemic brain injury. We subsequently turned to the design of neurostimulation circuits. Three critical features of neurostimulation devices are safety, programmability, and specificity. We conceived and implemented a neurostimulator architecture that utilizes a compact on-chip circuit for charge balancing (safety), digital-to-analog converter calibration (programmability) and current steering (specificity). Charge balancing accuracy was measured at better than 0.3%, the digital-to-analog converters achieved 8-bit resolution, and physiological effects of current steering stimulation were demonstrated in an anesthetized rat. Lastly, to implement a bidirectional neural interface, both the recording and stimulation circuits were fabricated on a single chip. In doing so, we implemented a low noise, ultra-low power recording front end with a high dynamic range. The recording circuits achieved a signal-to-noise ratio of 58 dB and a spurious-free dynamic range of better than 70 dB, while consuming 5.5 μW per channel. We demonstrated bidirectional operation of the chip by recording cardiac modulation induced through vagus nerve stimulation, and demonstrated closed-loop control of cardiac rhythm

A Closed-Loop Bidirectional Brain-Machine Interface System For Freely Behaving Animals

A brain-machine interface (BMI) creates an artificial pathway between the brain and the external world. The research and applications of BMI have received enormous attention among the scientific community as well as the public in the past decade. However, most research of BMI relies on experiments with tethered or sedated animals, using rack-mount equipment, which significantly restricts the experimental methods and paradigms. Moreover, most research to date has focused on neural signal recording or decoding in an open-loop method. Although the use of a closed-loop, wireless BMI is critical to the success of an extensive range of neuroscience research, it is an approach yet to be widely used, with the electronics design being one of the major bottlenecks. The key goal of this research is to address the design challenges of a closed-loop, bidirectional BMI by providing innovative solutions from the neuron-electronics interface up to the system level. Circuit design innovations have been proposed in the neural recording front-end, the neural feature extraction module, and the neural stimulator. Practical design issues of the bidirectional neural interface, the closed-loop controller and the overall system integration have been carefully studied and discussed.To the best of our knowledge, this work presents the first reported portable system to provide all required hardware for a closed-loop sensorimotor neural interface, the first wireless sensory encoding experiment conducted in freely swimming animals, and the first bidirectional study of the hippocampal field potentials in freely behaving animals from sedation to sleep. This thesis gives a comprehensive survey of bidirectional BMI designs, reviews the key design trade-offs in neural recorders and stimulators, and summarizes neural features and mechanisms for a successful closed-loop operation. The circuit and system design details are presented with bench testing and animal experimental results. The methods, circuit techniques, system topology, and experimental paradigms proposed in this work can be used in a wide range of relevant neurophysiology research and neuroprosthetic development, especially in experiments using freely behaving animals

On the application and generation of subsensory electrical nerve stimulation for the improvement of vibration perception in patients with HIV-related sensory neuropathy

This work investigates the application of Subsensory Electrical Noise Stimulation (SENS) to improve symptoms of HIV-related peripheral sensory neuropathy (HIVPN). HIV-PN occurs in roughly half of the 5 million people in South Africa with HIV. The disease has been shown to reduce quality of life and increase the risk of secondary ailments. Currently there is no treatment available. Previously, SENS has shown promise to improve tactile sensitivity in healthy populations and elderly individuals with peripheral neuropathic desensitisation. This work first establishes if SENS can improve the peripheral sensitivity of patients with HIV-PN, and secondly addresses practical aspects of using SENS in a therapeutic context. The vibrotactile sensitivity deficits of participants with HIV-PN and a matched control cohort is documented and analysed. It is found that HIV-PN participants have reduced sensitivity at all tested vibration frequencies (25 Hz, 50 Hz and 128 Hz), but especially at low frequencies. The interaction with vibration frequency indicates that HIV-PN may interact differently with different types of peripheral mechanoreceptors. SENS is then applied at four different amplitudes in an attempt to improve perception thresholds of the three vibration frequencies. SENS was shown to generally have a beneficial effect on 50 Hz vibration sensitivity for low SENS amplitudes. It had no effect, or a detrimental effect, at high SENS amplitudes, and also for 25 Hz and 128 Hz vibration frequencies. This work is also the first to document measures of pain with interventions of this type. No clear effects of SENS on sensations of pain were observed, which is a vital outcome if the therapy is to be developed further, since neuropathic pain is a frequent symptom of HIV-PN. The application of SENS as a practical therapy requires the accurate measurement of the participant’s electrical perception threshold, and a wearable device to apply the electrical signal on an ongoing basis. Research into the stability of electrical perception thresholds specifically aimed at subthreshold signals that would improve tactile sensitivity is presented. It was found that these thresholds vary wildly and correlated very little with possible explanatory variables, which introduces a new challenge for the development of SENS in future research. Currently there are no devices available to apply SENS in non-laboratory settings or for continuous use. The electronic design of a stimulator for using SENS as a wearable intervention is presented and characterised. The circuit is an efficient, low-power voltage to current converter that generates high voltages (120 V peak to peak) from a small, low-voltage rechargeable battery. The design and testing of control and instrumentation circuitry, as well as the addition of various safety and interface features is also documented. The battery life of the circuit is tested to operate for up to 33 hours and the circuit is tested to operate as expected in vivo. The results of this work demonstrate the potential viability of SENS as a therapy for HIV-PN, reveals the variability of electrical perception thresholds, explores the measures of pain for SENS interventions, and provides a complete and thoroughly tested design and implementation of an unparalleled electronic stimulator for nonlaboratory environments. The conclusions of this work form both a strong theoretical and practical basis for future SENS intervention research

Design of Integrated Neural/Modular Stimulators

Ph.DDOCTOR OF PHILOSOPH

Wireless Simultaneous Stimulation-and-Recording Device (SRD) to Train Cortical Circuits in Rat Somatosensory Cortex

The primary goal of this project is to develop a wireless system for simultaneous recording-and-stimulation (SRD) to deliver low amplitude current pulses to the primary somatosensory cortex (SI) of rats to activate and enhance an interhemispheric cortical pathway. Despite the existence of an interhemispheric connection between similar forelimb representations of SI cortices, forelimb cortical neurons respond only to input from the contralateral (opposite side) forelimb and not to input from the ipsilateral (same side) forelimb. Given the existence of this interhemispheric pathway we have been able to strengthen/enhance the pathway through chronic intracortical microstimulation (ICMS) in previous acute experiments of anesthetized rats. In these acute experiments strengthening the interhemispheric pathway also brings about functional reorganization whereby cortical neurons in forelimb cortex respond to new input from the ipsilateral forelimb. Having the ability to modify cortical circuitry will have important applications in stroke patients and could serve to rescue and/or enhance responsiveness in surviving cells around the stroke region. Also, the ability to induce functional reorganization within the deafferented cortical map, which follows limb amputation, will also provide a vehicle for modulating maladaptive cortical reorganization often associated with phantom limb pain leading to reduced pain. In order to increase our understanding of the observed functional reorganization and enhanced pathway, we need to be able to test these observations in awake and behaving animals and eventually study how these changes persist over a prolonged period of time. To accomplish this a system was needed to allow simultaneous recording and stimulation in awake rats. However, no such commercial or research system exists that meets all requirements for such an experiment. In this project we describe the (1) system design, (2) system testing, (3) system evaluation, and (4) system implementation of a wireless simultaneous stimulation-and-recording device (SRD) to be used to modulate cortical circuits in an awake rodent animal model

Improving the mechanistic study of neuromuscular diseases through the development of a fully wireless and implantable recording device

Neuromuscular diseases manifest by a handful of known phenotypes affecting the peripheral nerves, skeletal muscle fibers, and neuromuscular junction. Common signs of these diseases include demyelination, myasthenia, atrophy, and aberrant muscle activity—all of which may be tracked over time using one or more electrophysiological markers. Mice, which are the predominant mammalian model for most human diseases, have been used to study congenital neuromuscular diseases for decades. However, our understanding of the mechanisms underlying these pathologies is still incomplete. This is in part due to the lack of instrumentation available to easily collect longitudinal, in vivo electrophysiological activity from mice. There remains a need for a fully wireless, batteryless, and implantable recording system that can be adapted for a variety of electrophysiological measurements and also enable long-term, continuous data collection in very small animals. To meet this need a miniature, chronically implantable device has been developed that is capable of wirelessly coupling energy from electromagnetic fields while implanted within a body. This device can both record and trigger bioelectric events and may be chronically implanted in rodents as small as mice. This grants investigators the ability to continuously observe electrophysiological changes corresponding to disease progression in a single, freely behaving, untethered animal. The fully wireless closed-loop system is an adaptable solution for a range of long-term mechanistic and diagnostic studies in rodent disease models. Its high level of functionality, adjustable parameters, accessible building blocks, reprogrammable firmware, and modular electrode interface offer flexibility that is distinctive among fully implantable recording or stimulating devices. The key significance of this work is that it has generated novel instrumentation in the form of a fully implantable bioelectric recording device having a much higher level of functionality than any other fully wireless system available for mouse work. This has incidentally led to contributions in the areas of wireless power transfer and neural interfaces for upper-limb prosthesis control. Herein the solution space for wireless power transfer is examined including a close inspection of far-field power transfer to implanted bioelectric sensors. Methods of design and characterization for the iterative development of the device are detailed. Furthermore, its performance and utility in remote bioelectric sensing applications is demonstrated with humans, rats, healthy mice, and mouse models for degenerative neuromuscular and motoneuron diseases

Knee extension with less hip flexion: biomechanical and evoked EMG analysis during selective surface stimulation of the quadriceps

During FES cycling when the Quadriceps muscles are activated both knee extension and hip flexion moments occur simultaneously, decreasing the total power output. Of the three superficial muscles, Rectus femoris is a biarticular muscle that produces both a knee extension and a hip flexion, while Vastus lateralis and Vastus medialis are only knee extensors. This thesis is an investigation whether, using surface stimulation, selective stimulation of the Vastii can produce knee extension moment with less hip flexion. A system was developed for measurement of the joint moments and evoked myoelectric response in these three muscles, while seated subjects were stimulated. The dynamometer measures the magnitude and position of two forces that restrain the leg, from which joint moments are calculated. The design and construction of the hardware, electronics and software is presented. Validation of the dynamometer against known moments produced with a spring-loaded dummy leg showed good correlation. The influence of random and systematic errors on the estimated joint moments indicate that the dynamometer should be used for comparing the responses for different electrode configurations within single sessions. The close proximity of the EMG recording electrodes to the stimulating electrodes causes artefact that obscures the M-wave. This was partly overcome by amplifying with a current conveyor circuit, and by a novel biphasic stimulator with pulse width ratio adjustment. The design and construction of both stimulator and amplifier are discussed, also the mechanisms causing the artefact (voltage gradient, skin-electrode interface and common mode voltage). A study with ten able-bodied subjects was performed. EMG analysis showed that it is possible to selectively stimulate the Vastii and this does reduce hip flexion moment, however beside the inevitable reduction of knee extension moment, the reduction of the hip flexion is less than expected, perhaps due to stimulation of other muscles of the anterior thigh